Expanding the Utility of Severe Combined Immuno-Deficient (SCID) Pig Models

扩大严重联合免疫缺陷 (SCID) 猪模型的用途

• 批准号: 9060414
• 负责人: Christopher Tuggle
• 金额: $ 65.88万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060414
• 关键词: Address; Age-Months; Alleles; Allogenic; Amino Acid Sequence; Animal Model; Animals; Area; B-Lymphocytes; Biology; Bone Marrow; Bone Marrow Transplantation; Bone Regeneration; Cancer cell line; Cardiac; Cell Therapy; Cells; Clinic; Counseling; Development; Engraftment; Family suidae; Gene Mutation; Generations; Genes; Genetic; Genetic Code; Goals; Heart Research; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterozygote; Human; Human Biology; Immune; Immune system; Immunophenotyping; Inbreeding; Institutes; Knowledge; Letters; Life; Maintenance; Mesenchymal Stem Cells; Modeling; Mus; Mutate; Mutation; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Killer Cells; Neonatal; Outcome; Outcomes Research; Patients; Peptide Sequence Determination; Phenotype; Physiology; Population Genetics; Pre-Clinical Model; Preclinical Testing; Preparation; Procedures; Proteins; Protocols documentation; Regenerative Medicine; Research; Research Personnel; Research Project Grants; Residual state; Resources; Safety; Scientist; Splice-Site Mutation; Stem Cell Research; Stem cells; Study models; T-Lymphocyte; Terminator Codon; Testing; Therapeutic; Translating; Translations; Transplantation; United States National Institutes of Health; Variant; Work; Wound Healing; Xenograft procedure; adaptive immunity; artemis; base; biocontainment facility; cartilage regeneration; cohort; comparative; design; gene product; genetic resource; graft vs host disease; human stem cells; improved; in vivo Model; innovation; interest; leukemia/lymphoma; mouse model; mutant; novel; null mutation; pathogen; pre-clinical; pre-clinical research; public health relevance; stem cell therapy; translational medicine; vaccine evaluation

DESCRIPTION (provided by applicant): The promise of stem cell-based therapies is currently not being fully realized due to the lack of appropriate pre-clinical animal models. Consequently, there remains a critical need to develop better animal models that better translate results from preclinical research trials to the patient. Scientific advancements addressing this problem have been realized through the identification of a naturally occurring Severe Combined Immuno- Deficient (SCID) line of pigs. The SCID pig model has been preliminarily characterized as both T and B lymphocytes deficient and thus is deficient in adaptive immunity. The pig is known to be an excellent model for human biology due to similarities in size, physiology and genetic code; and this novel SCID model has been successfully engrafted with multiple human cancer cell lines, indicating high potential as an in vivo model for many areas of regenerative medicine testing. We have received multiple requests and interest in obtaining this model. The research areas of these interested scientists spans many areas of regenerative medicine research, from cardiac progenitor cell therapies to cartilage regeneration studies, to the use of mesenchymal stem cells for bone regeneration and wound repair, to improving treatment of graft versus host disease in hematopoietic stem cell (HSC) transplants. A pig SCID model will have a specific positive impact in that it will provide researchers with alternative and comparative models for such stem cell research. Our long-term goal is to create validated SCID models for broad use in preclinical testing of such stem cell based therapies. The specific objectives of this application are to further develop this model for regenerative medicine testing, as well as improve its ability to engraft human cells into the bone marrow so that a human immune system can develop. Such an advanced model could be broadly used for vaccine testing and the study of human-specific pathogens. To maximize the broad use of these models, we will further develop protocols and design and test biocontainment facilities for practical utilization of our current pi lines. Our rationale for the proposed research is that the SCID pig is physiologically and phylogenetically more similar to humans than the mouse and therefore may more accurately reflect how proposed stem cells will survive and function in humans. This project is innovative because a SCID pig model has not been fully developed, and development of such model may result in significantly and rapidly advancing the fundamental knowledge of SCID into translational medicine capable of accelerating regenerative medicine research. With regard to expected outcomes, the successful completion of this project will create multiple genetic resources and associated animal procedures that will be highly desirable for SCID based modeling for research projects focused on the efficacy of stem cell therapeutics. Thus these unique resources are expected to have a significant impact in accelerating the translation of regenerative medicine research into the clinic.

描述（由申请人提供）：由于缺乏适当的临床前动物模型，目前尚未完全实现基于干细胞疗法的承诺。因此，仍然需要开发更好的动物模型，以更好地将临床前研究试验的结果转化为患者。通过鉴定出天然存在严重的免疫缺陷（SCID）猪线，已经实现了解决此问题的科学进步。 SCID猪模型的初步表征为T和B淋巴细胞缺乏，因此缺乏适应性免疫。由于大小，生理和遗传密码的相似之处，猪是人类生物学的绝佳模型。这种新型的SCID模型已成功地植入了多个人类癌细胞系，这表明作为再生医学测试许多领域的体内模型的潜力很高。我们收到了多个请求和获取该模型的兴趣。这些感兴趣的科学家的研究领域跨越了再生医学研究的许多领域，从心脏祖细胞疗法到软骨再生研究，再到使用间质干细胞用于骨再生和伤口修复，再到血肿干细胞（HSC）移植的宿主与宿主疾病的治疗。猪SCID模型将产生特定的积极影响，因为它将为研究人员提供此类干细胞研究的替代性和比较模型。我们的长期目标是创建经过验证的SCID模型，以在此类基于干细胞的疗法的临床前测试中进行广泛使用。本应用程序的具体目标是进一步开发用于再生医学测试的模型，并提高其能力 将人类细胞植入骨髓中，以便可以发展为人类免疫系统。这样的先进模型可广泛用于疫苗测试和人类特异性病原体的研究。为了最大程度地利用这些模型，我们将进一步开发协议，设计和测试生物内在设施，以实际利用当前的PI系。我们对拟议的研究的理由是，SCID猪在生理和系统发育上与人类更相似，因此可能更准确地反映了拟议的干细胞在人类中的生存和功能。该项目具有创新性，因为SCID猪模型尚未得到充分开发，并且这种模型的开发可能会导致SCID的基本知识大大发展为能够加速再生医学研究的转化医学。关于预期的结果，该项目的成功完成将创建多种遗传资源和相关的动物程序，这些程序对于基于SCID的建模非常适合针对干细胞疗法功效的研究项目。因此，这些独特的资源有望在加速再生医学研究为诊所的翻译中产生重大影响。